Chronic Constipation in Adults: Contemporary Perspectives and Clinical Challenges. 2: Conservative, Behavioural, Medical and Surgical Treatment

Received: 23 July 2020 | Revised: 5 December 2020 | Accepted: 13 December 2020 DOI: 10.1111/nmo.14070

REVIEW

Chronic constipation in adults: Contemporary perspectives and clinical challenges. 2: Conservative, behavioural, medical and surgical treatment

1NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK 2School of Medicine, University of Nottingham and Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK 3Department of Surgery, University of Sheffield, Sheffield, UK 4Division of Gastroenterology, University of Verona, AOUI Verona, Verona, Italy 5Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 6Department of Nutritional Sciences, King’s College London, London, UK 7University of Southampton NHS Trust, Southampton, UK 8GI Physiology Unit, UCL & UCLH, London, UK 9Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland 10Digestive Function: Basel, Laboratory and Clinic for Motility Disorders and Functional Gastrointestinal Diseases, Centre for Integrative Gastroenterology, Klinik Arlesheim, Arlesheim, Switzerland 11Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, UK 12Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, UK 13Department of Colorectal Surgery, Barts health NHS Trust, London, UK 14Tertiary Referral Pelvic Floor and Incontinence Centre, Regional Hospital Treviso, University of Padua, Padua, Italy 15Durham Bowel Dysfunction Service, Old Trust Headquarters, University Hospital of North Durham, Durham, UK 16National Bowel Research Centre and GI Physiology Unit, Centre for Neuroscience, Surgery & Trauma, Blizard Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK 17Centre for Colorectal Disease, St Vincent’s University Hospital, Dublin, Ireland 18Lynda K and David M Center for Gastrointestinal Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas, USA 19Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 20Guy's and St Thomas, NHS Foundation Trust, London, UK

Abbreviations: 5-HT, 5-hydroxytryptamine; ACE, anterograde continence enema; CC, chronic constipation; CI, confidence interval; CSBM, complete spontaneous bowel movements; FC, functional constipation; FMT, fecal microbiota transplantation; GC-C, guanylate cyclase-C; hERG, human ether-a-go-go-related gene; IBAT, ileal bile acid transporter; IBS, irritable bowel syndrome; IBS-C, irritable bowel syndrome with constipation; MDT, multidisciplinary team; NHE3, sodium-hydrogen exchanger 3; RCT, randomized controlled trials; SGLT1, sodium-glucose linked transporter 1; SMD, standardized mean difference; SNM, sacral neuromodulation; SRMA, systematic review and meta-analysis; STARR, stapled transanal rectal resection; TAI, transanal irrigation.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2020 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.

wileyonlinelibrary.com/journal/nmo | 1 of 15 Neurogastroenterology & Motility. 2021;00:e14070. https://doi.org/10.1111/nmo.14070 2 of 15 | CORSETTI et al.

Correspondence Maura Corsetti, Nottingham Digestive Abstract Diseases Biomedical Research Centre, Background: Chronic constipation is a prevalent disorder that affects quality of life of Queens Medical Centre – D Floor, West Block, Derby Road, Nottingham, NG7 patients and consumes resources in healthcare systems worldwide. In clinical practice, 2UH, UK. it is still considered a challenge as clinicians frequently are unsure as to which treat- Email: [email protected] ments to use and when. Over a decade ago, a Neurogastroenterology and Motility journal supplement devoted to the investigation and management of constipation was published (Neurogastroenterol Motil 2009;21(Suppl 2):1). In October 2018, the 3rd London Masterclass, entitled “Contemporary management of constipation” was held. The faculty members of this symposium were invited to write two reviews to present a collective synthesis of talks presented and discussions held during this meeting. The first review addresses epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. Purpose: The present is the second of these reviews, providing contemporary perspectives and clinical challenges regarding behavioral, conservative, medical, and surgical treatments for patients presenting with constipation. It includes a management algorithm to guide clinical practice.

KEYWORDS algorithm, constipation, IBS-C, treatment

1 | INTRODUCTION 2 | BEHAVIORAL AND CONSERVATIVE INTERVENTIONS Chronic constipation (CC) remains a clinical challenge, with outcomes to a variety of interventions (behavioral, conservative, medi- 2.1 | Behavioral management cal, and surgical) that are frequently suboptimal. Over a decade ago, a Neurogastroenterology and Motility journal supplement devoted Behavioral modification is a commonly recommended, but inconsist- to the investigation and management of constipation was pub- ently applied, first-line treatment for patients with CC. It generally lished, disseminating all themes covered during a preceding two- includes patient education about the nature of their condition, advice day meeting held in London [1]. In October 2018, the 3rd London regarding lifestyle modification, toilet habit training, and instruction Masterclass, entitled “Contemporary management of constipation” on defecation dynamics. The extent to which behavioral modifica- was held, again over 2 days, and again boasting a world-renowned tion helps individual patients is difficult to quantify, perhaps inevita- faculty. By way of dissemination, two side-by-side review articles bly given the nature of such a composite intervention; accordingly, have been produced, which represent a collective synthesis of talks clinical trials of the individual components that constitute behavioral presented and discussions held during this meeting. The authors modification therapy do not exist, though they are described below were all invited faculty members. These reviews provide not only to help the reader understand the patient approach required. an update on topics addressed in the previous journal supplement, Establishing rapport between patient and professional is a key but also a state-of-the-art overview of the clinical management of component to any educational initiative. Empathic reassurance is this prevalent and often difficult-to-treat condition. Areas for fu- also key to helping the patient recognize that they will be supported ture research are additionally highlighted. The first review article along their journey to improve compliance. addresses epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. This “sister” review addresses the contemporary perspectives and clinical challenges regarding be- 2.2 | Lifestyle advice havioral, conservative, medical, and surgical treatments in patients presenting with constipation. It includes a management algorithm The average adult in the UK eats 60% (18 g) of the recommended to guide clinical practice. As constipation can present as functional daily fiber intake [2]. Irregular eating habits and low-fiber diets are constipation (FC) or irritable bowel syndrome with constipation considered risk factors for constipation [3,4]. (IBS-C), where available, evidence for both is presented. When not Patients with CC are often told to increase dietary fiber; guide- specified, data should be assumed to relate to patients with CC and lines suggest supplementation with 25 g to 30 g per day [5, 6], but not to a specific subtype. it is important to understand the mechanism of action since there CORSETTI et al. | 3 of 15 are some significant side effects, which may be reduced by gradual Thus, it appears that fibers that alleviate constipation act on both titration. Insoluble fibers, such as wheat bran, increase small bowel the small and large intestine to increase stool water, accelerate tran- water content [7], and accelerate small bowel [8] and colonic transit sit, and facilitate defecation. [9], thereby increasing stool frequency [10, 11]. Bran contains sub- Although a diet low in fermentable carbohydrates (FODMAPs) stantial amounts of fermentable fiber, which may worsen some as- has been shown to improve symptoms of irritable bowel syndrome sociated symptoms in CC, including abdominal pain, flatulence, and in several randomized controlled trials [27, 28], there is a lack of con- bloating [12]. Soluble fiber, such as psyllium, increases small bowel vincing evidence on its effectiveness in IBS-C specifically, and its and colonic water content, but not colonic gas, with an increase in impact in FC has not been investigated. stool bulk and frequency [13]. When compared to psyllium in a RCT, In dehydrated patients, increasing fluids will improve constipa- a mixture of soluble and insoluble plum fiber appeared equally effec- tion, but it is important to recognize that patients with CC are not tive in patients with CC [14]. the same as patients with acute dehydration physiologically; an Despite this, support for the use of fiber in CC is not strong. A adequate fluid intake (up to 2 L/day) will increase the efficacy of systematic review identified only six RCTs, four of which compared a high-fiber diet [29]. Overhydration will not improve constipation soluble fiber with placebo, and two insoluble fiber [15]. None was as there is no association between fluid intake and constipation at low risk of bias. Compared with placebo, psyllium led to signifi- [29] Nevertheless, it is worth mentioning that four randomized, cant improvements in global symptoms, abdominal pain and discom- double-blind, placebo-controlled studies have demonstrated that fort, and straining in one RCT [16]. In another trial, psyllium led to magnesium sulfate-rich natural mineral waters improved stool con- a significant increase in stool frequency, from 2.9 stools per week sistency and number of bowel movements in patients with CC, in at baseline to 3.8 after treatment; there was no improvement with association with a very good safety profile. This effect is probably placebo [17]. One RCT of wheat bran reported reduced straining, the result of an osmotic mechanism of action, and efficacy was more but this was no different than with placebo [18], and a trial of rye noticeable with a higher total concentration of magnesium and sul- bread versus a low-fiber bread demonstrated a significantly higher fate [30]. number of stools per day with rye bread and softer stools [19]. A There is little evidence that increasing physical activity improves meta-analysis of seven placebo-controlled trials, published in 2015, constipation. Physical activity can decrease colonic transit time and reported that the relative risk of treatment success with fiber was reduce symptoms of constipation in the elderly, but has not been significantly higher (1.71; 95% CI 1.20–2.42), stool frequency was shown to have any positive effect on constipation in young adults significantly increased (SMD = 0.39; 95% CI 0.03–0.76), and stool [31, 32]. The minor influence of physical activity on bowel function consistency improved (SMD = 0.35; 95% CI 0.04–0.65), but again is highlighted by a recent North American survey [33]. Data from noted that the quality of evidence was low [20]. Both these system- nearly 10,000 individuals suggested an odds ratio of less than two atic reviews identified a need for further large placebo-controlled for physical activity reducing constipation, and these weak associa- trials of fiber in CC. With regard to effect of fiber supplementation tions did not persist on multivariate analysis [33]. in differing pathophysiological subgroups, it is worth noting that a study conducted in 149 patients with CC demonstrated that 80% of patients with slow transit and 63% of patients with a disorder of 2.3 | Bowel (habit) retraining defecation did not respond to dietary fiber treatment [21]. The sit- uation is similar in IBS-C. Although there is a meta-analysis of seven Patients are often advised to defecate when the urge is felt, ide- placebo-controlled trials of psyllium showing a benefit in IBS [22], ally in the morning and after meals to take advantage of the gastro- none have formally evaluated the efficacy of fiber in any of the IBS colic response, when colonic motor activity is at its highest. This is symptom subgroups. based on observations of people with normal bowel habits [34]. A The laxative effect of various fruits in CC is well recognized. In recent survey found that bowel retraining was a widely employed one small crossover trial comparing dried plums with psyllium in 40 therapeutic strategy, but often without formal training of practition- patients, the number of CSBMs was significantly higher, and stool ers and without standardized protocols [35]. The intervention was consistency scores significantly improved, with dried plums [23]. thought to be effective, but since habit retraining is often part of However, effects on global symptoms and straining were no differ- biofeedback therapy (see section below), there is no evidence of the ent between the two treatment arms, and there was no placebo. A benefit of such retraining in isolation. placebo-controlled trial of fig paste in 80 patients with CC demonstrated reduced colonic transit time, and significant improvements in abdominal discomfort and stool form [24]. Finally, an RCT of kiwifruit 2.4 | Biofeedback extract reported that defecation frequency increased significantly, and painful defecation and abdominal pain were significantly lower, Biofeedback is defined as a conditioning treatment where infor- compared with placebo [25]. Stool softening and increased stool fre- mation about a physiological process is converted by dedicated quency in a small mechanistic trial of kiwifruit were associated with devices to a simple signal to enable the patient to learn to control an increase in T1, a validated MRI marker of stool water content [26]. the disordered defecation process [36]. Biofeedback is considered 4 of 15 | CORSETTI et al. appropriate when the voluntary control of responses can be learned 2.6 | Psychological therapies with the aid of systematic information about functions not usually monitored at a conscious level [36]. Initial open-label trials sug- A recent meta-analysis reported that psychological therapies are gested that biofeedback was equally effective in slow-transit consti- efficacious for IBS, with CBT-based interventions and gut-directed pation and in evacuation disorders [37, 38]. However, a subsequent hypnotherapy having the largest evidence base and greatest efficacy study demonstrated that biofeedback ameliorated symptoms and long-term [54]. However, whether these are effective in the specific accelerated bowel transit in over 70% of slow-transit constipation subtype of IBS-C or in patients with FC has not been examined. due to dyssynergia, while patients with an isolated impairment of gut transit did not improve [39]. Three succeeding randomized controlled trials further addressed the specific therapeutic contribution 2.7 | Areas for future research of biofeedback therapy for dyssynergia and showed that biofeedback therapy was superior to other treatments for dyssynergic def- 1. Lifestyle modifications are always reported as first-line treatment ecation including sham biofeedback, placebo pills, diazepam, and in patients with constipation, but the evidence regarding their osmotic laxatives [40–42]. Improvements in measures of anorectal efficacy is not strong. physiology correlated with successful outcomes, and no side ef- 2. Clinical investigation of the laxative effect of magnesium sulfate- fects occurred during 4 years of follow-up [40–43]. In these trials, a rich natural mineral waters is a very recent field of research. complex protocol addressing all specific mechanisms for defecation, Additional studies comparing efficacy and safety with that of including posture and pushing effort, was employed [40–42]. Other other treatments, both in FC and in IBS-C, may be of interest. studies have shown that home-based and shorter biofeedback pro- 3. It would be interesting to understand whether combining viscous tocols appear to be effective in improving constipation due to func- fiber with agents with a prokinetic effect might improve tolerabil- tional defecation disorders [44, 45]. Factors that predict successful ity and efficacy. outcome of biofeedback therapy are harder stool consistency, digi- 4. Biofeedback is a cumbersome procedure, and dedicated machin- tal maneuvers to facilitate defecation, shorter duration of laxative ery is needed. Whether simple bowel retraining techniques could use, higher resting anal sphincter pressure, and failure to expel a be non-inferior to instrumented biofeedback for functional def- rectal balloon during rectal balloon expulsion test [46]. The patient's ecation disorders remains to be evaluated. willingness to participate and the therapist's skill and motivation are 5. We still do not know whether TAI has a long-term role in patients also relevant to a successful outcome [46]. No randomized studies with CC; studies comparing TAI with biofeedback are lacking. have evaluated so far whether biofeedback has different effect in 6. Whether psychological therapies are effective in the specific sub- FC versus IBS-C. group of IBS-C or in FC remains to be evaluated.

2.5 | Transanal irrigation 3 | MANIPULATING THE MICROBIOME

Transanal irrigation (TAI) is a minimally invasive treatment option 3.1 | Prebiotics for patients with CC refractory to conservative therapy [47]. TAI is intended to assist the evacuation of stool from the rectum and dis- Prebiotics are defined as a substrate that is selectively utilized by tal colon by introducing tepid water via the anus. The method has host microorganisms conferring a health benefit [55]. In another been demonstrated to be superior to standard bowel care in pa- context, many of these substances are termed fermentable oligo-, tients with constipation secondary to a neurological disorder [48]. di-, and monosaccharides and polyols (FODMAPs). Compared with In these patients, the use of TAI improves quality of life [49], reduces probiotics, which introduce exogenous bacteria into the human time spent on bowel management compared with previous meth- colon, prebiotics stimulate the preferential growth of a limited num- ods [49, 50], and reduces episodes of fecal incontinence [50]. More ber of health-promoting commensal microbiota already residing in than one system is available, and the technology is well tolerated by the colon and, especially, but not exclusively, lactobacilli and bifido- most patients [47, 51]. Furthermore, TAI has been shown to result in bacteria [56]. Examples of prebiotics include the human milk oligo- a lower total cost to society than standard bowel management [48]. saccharides in breastmilk, the inulin-type fructans, which are linked The exact mechanism of action is unclear, although there is likely to by β (2–1) bonds that limit their digestion by enzymes in the small be a degree of “flushing” and/or stimulation of peristaltic contrac- intestine, and galactooligosaccharides. Inulin-type fructans are pre- tions [52]. Regular use of TAI can aid emptying of the bowel and help sent in many edible cereals, fruits, and vegetables, including wheat, to re-establish control of bowel function by choosing the time and onion, chicory, garlic, leeks, and artichokes, with galactooligosaccha- place of evacuation, thus re-instating a more predictable evacuation. rides being present in legumes [57]. However, to date no studies have considered the cost-effectiveness, In a meta-analysis of 47 randomized controlled trials (RCTs), inu- including prospectively collected health-related quality of life data, lin-type fructan prebiotics were shown to increase stool frequency for long-term use of TAI in patients with CC [53]. (+0.28 stools per day, p < 0.001), an effect seen particularly with CORSETTI et al. | 5 of 15 short-chain fructans (+0.36 stools per day, p < 0.001), although the CC, variable treatment duration, lack of consistency in outcomes, trials were in mixed populations of healthy controls or patients [58]. lack of validated assessment techniques, and selective outcome Fewer clinical trials have been performed investigating prebiotics reporting. Similarly, SRMAs are burdened by high heterogeneity specifically in CC [58, 59]; a meta-analysis of five RCTs (involving and risk of bias, rendering their interpretation and generalization a mere 199 patients) confirmed that prebiotics resulted in a small difficult. increase in stool frequency (+1.01 stools/week, 95% CI 0.04–1.99) Therefore, the use of probiotics for the treatment of constipa- [60]. Subgroup analysis suggested effects for galactooligosaccha- tion should continue to be considered as investigational, and fur- rides on stool frequency, stool consistency, ease of defecation, and ther high-quality RCTs are needed to confer confident conclusions abdominal pain [60]. However, in meta-analysis of fiber specifically regarding their effectiveness. Data collected in IBS patients do not in patients with constipation, two trials of prebiotics alone and two allow us to conclude whether there is a particular IBS subtype that is trials of prebiotics in conjunction with other fibers failed to show an more likely to benefit [61]. impact on dichotomous response, stool frequency, or stool consistency [58]. No studies have evaluated the role of prebiotics specifically in IBS-C patients [61]. 3.3 | Synbiotics

A synbiotic, the combined use of a probiotic and a prebiotic, aims 3.2 | Probiotics to increase the survival and activity of proven probiotics in vivo, as well as stimulating indigenous bifidobacteria and lactobacilli. In an Probiotics are live microorganisms that, when administered uncontrolled pilot study, Valerio and colleagues fed artichokes (con- in adequate amounts, confer a health benefit to the host [62]. taining inulin-type fructans) and Lactobacillus paracasei to healthy Unfortunately, the interpretation of available data on many probi- volunteers and noted a reduction in abdominal distension and the otic products is confounded by variability in strain selection, dose, sensation of incomplete evacuation [69]. A more recent meta-analy- delivery vehicle, and limited information regarding evaluation of sis of eight RCTs involving a total of 825 people with CC concluded viability and efficacy. Indeed, many “probiotic” products do not that synbiotics resulted in a small increase in stool frequency (+1.15 even meet the above-stated definition in that they: (a) do not con- stools/week, 95% CI 0.58–1.71), improved stool consistency (stand- tain live organisms or have not been adequately tested to ensure ardized mean difference (SMD) 0.63, 95% CI 0.33–0.92), reduced their viability in the conditions or for the length of time that is whole gut transit time (−13.5 h, 95% CI −26.6 to −0.5), and also re- claimed, and/or (b) have not been confirmed to confer a health duced straining and bloating [59]. However, it should be noted that benefit in humans. only one trial was deemed to be at low risk of bias across all domains There are several animal and human studies suggesting that with a notable lack of intention-to-treat analysis. The interpretation probiotics may regulate gut motility and improve constipation-re- of synbiotic RCTs is also hampered by the impossibility of defining lated outcomes via their impact on the gut microbiota and their the active agent(s)—prebiotic, probiotic, or both. There are insuffi- by-products, and on the nervous and immune system [63–65]. cient data on the use of synbiotics in IBS-C [61, 71]. Systematic reviews have demonstrated variable results for different probiotic strains in both children [66, 67] and adults [68]. A systematic review of the use of probiotics among the elderly 3.4 | Fecal microbiota transplantation with constipation showed a modest benefit for probiotics [68]; however, the authors stressed that caution needs to be exercised Fecal microbiota transplantation (FMT) has also been investigated in the interpretation of the available data. Another systematic as a potential management strategy for CC. A RCT of 60 individu- review and meta-analysis (SRMA) of 14 RCTs demonstrated that als with slow-transit constipation showed that a significantly higher Bifidobacterium lactis species significantly increased stool fre- proportion had 3 or more complete spontaneous bowel movements quency (+1.5 stools/week, 95% confidence interval [CI] 0.7–2.3) (CSBMs) per week following FMT compared with standard treat- and improved symptoms in people with CC, whereas Lactobacillus ment (37% vs. 13%; p = 0.04), with improvements in stool consist- casei Shirota did not; this suggested a potential beneficial effect ency and gut transit time also demonstrated [72]. Additionally, there of probiotics in constipation in favor of B. lactis. However, RCTs is emerging evidence to support a role for FMT in the management published subsequent to this systematic review have shown no of IBS, including IBS-C [73]. Nevertheless, the use of FMT in CC or improvement in constipation symptoms following the adminis- IBS-C is still investigational. tration of specific B. lactis strains, including B. lactis HN019 that had been previously shown to improve constipation in a smaller study [69, 70]. Such conflicting data may be attributed to study 3.5 | Areas for future research methodologies. Several studies are of low-quality and suffer from limitations in design and execution, including lack of ade- 1. Characterization of the colonic microbiome in FC and IBS-C quate statistical power, use of inconsistent diagnostic criteria of with control for confounding factors. 6 of 15 | CORSETTI et al.

2. Does the baseline microbiome in a constipated individual predict at the mucosal level to the active moiety, which acts to stimulate gut response to various interventions? peristalsis. Both drugs showed significant advantage over placebo in 3. High-quality studies of interventions that modulate the microbi- both bowel symptoms and quality-of-life measures. However, side ome in FC and IBS-C. effects of abdominal pain and diarrhea were reported, and the number needed to treat, 3, was similar to the number needed to harm [6]. No large, randomized placebo-controlled studies have tested the 4 | MEDICAL THERAPIES efficacy of these laxatives in IBS-C. The stool softener class of laxatives (docusate, liquid paraffin) 4.1 | Laxatives has been compared with osmotic agents and found to be slightly less effective than the osmotic agents, and—especially with liquid There are a range of laxatives available, both over the counter paraffin—be associated with more adverse events [84, 85]. As such, and prescribed. These are classified according to their primary they are more often used as adjuvant drugs when patients report mechanism of action: bulking agents (see lifestyle advice); stool hard stools despite use of other agents [84, 85]. Again, no large, softeners; stimulants; and osmotic agents. Nevertheless, despite randomized placebo-controlled studies have tested the efficacy of being the mainstay of management of CC, high-quality clinical tri- these laxatives either in FC or in IBS-C. Even though enemas are fre- als of laxatives are scarce. A recent meta-analysis [74] identified quently used in patients with constipation, there are no controlled only four studies of laxatives of sufficient rigor and duration to studies of their efficacy or safety. In contrast, three short-term be assessed. (7–21 days) controlled studies have reported the benefit of potas- A brief discussion on the challenges associated with laxative use sium tartrate and sodium bicarbonate suppositories in improving in the setting of CC is worth bearing in mind. While laxatives can “dyschezia” [86–88]. be very effective in the acute setting, long-term use can be associ- Clinical trials tend to be short for what is often a lifelong con- ated with the development of tolerance and reduced response [75]. dition. A global survey identified that approximately half of all con- Poor adherence is often seen, and this is often related to the unpre- stipated patients remain dissatisfied with their current laxatives, dictability of onset and offset of effect of these agents, which all related to poor efficacy and adverse effects [89]. This highlights the depend on their contact time with the mucosa [76]. Development importance of tailoring laxatives to symptom response and monitor- of side effects is also a frequent issue for patients; typically, stool ing the patient to confirm adequate response [90]. looseness, urgency, and abdominal cramps are underlying symptoms that may be exacerbated by laxative use [76]. A final complication for the prescriber is that the clinical trials of laxatives are often of short 4.2 | Prokinetics duration and with endpoints that are not clinically meaningful for patients, such as bowel movement frequency and stool consistency Serotonin (5-hydroxytryptamine; 5-HT) receptors are abundant in [76]. Qualitative analyses have suggested that quality of life, predict- the gut and involved in both motility and sensation; of these, the ability, and time taken in bowel management are of greater impact 5-HT4 receptor has been most closely associated with the promo- on patients’ well-being [77]. tion of intestinal motility and transit and a number of agonists have Osmotic laxatives are cited in guidelines as the first-choice main- been developed. The first of these, cisapride, an upper gut proki- tenance therapy for CC [75, 78]. Two of the four placebo-controlled netic, was shown to have some efficacy in constipation [91], but lack studies identified in the above review used PEG with electrolytes of selectivity and interactions with the human ether-a-go-go-related as the osmotic agent [6] and demonstrated good efficacy for in- gene (hERG) channel led to the worldwide withdrawal of the drug creasing stool frequency and good perceived safety. Accumulation because of the occurrence of hERG channel-mediated cardiac ar- of glycol derivatives was raised as a possibility in pediatric practice, rhythmias [92]. Subsequently, tegaserod was developed to treat CC but this has not been demonstrated when formally investigated [79]. [93] and IBS-C [94] and was granted approval for these indications When compared to other osmotic agents (specifically, lactulose), a in some countries. Ultimately, it was withdrawn because of a small meta-analysis demonstrated that PEG was superior to lactulose in excess of cardiovascular ischemic events, the pathogenesis of which terms of improving stool frequency, stool consistency, relief of ab- remains unclear [92]. Recently, tegaserod was reintroduced in the dominal pain, and reducing use of other laxatives [80]. A less-used United States for the treatment of women with IBS-C. osmotic agent is magnesium hydroxide; clinical trials have shown no In contrast to cisapride and tegaserod, prucalopride is a difference between outcomes with PEG or such magnesium salts high-affinity, highly selective 5-HT4 agonist with low affinity ⁺ [81, 82]. In IBS-C, PEG has been found to improve constipation but for the hERG-K cardiac channels [95]. This 5-HT4 receptor af- not pain [83]. finity and sensitivity confers greater efficacy for prucalopride If symptoms persist, stimulant laxatives such as senna, bisaco- and explains why it has not been shown to be arrhythmogenic dyl, or sodium picosulfate are recommended in clinical guidelines [95]. Prucalopride promotes colonic motility and transit and has [75, 78]. Use of the latter two is supported by placebo-controlled trial been studied in seven large (≥300 patients in each), multicenter, evidence [6]. They are both prodrugs, which need to be metabolized double-blind, placebo-controlled trials; all but one showed that CORSETTI et al. | 7 of 15 prucalopride significantly improved bowel function, reduced con- and in IBS-C [75, 101]. Reflecting its negligible systemic absorption, stipation-related symptoms, and improved patient satisfaction the main adverse event experienced in these studies has been diar- and constipation-related quality of life [96]. These studies enrolled rhea [101]. The recommended dose for CC and IBS-C is respectively patients not responsive to laxatives, with a therapeutic gain over 145 and 290 µg once daily, but only the second dosage is available placebo being around 20%. The most common adverse effects in Europe [75]. were headache (25%–30% prucalopride; 12%–17% placebo), nau- Plecanatide has also been shown to be effective in a phase III sea (12%–24%; 8%–14%), abdominal pain or cramps (16%–23%; study in CC and in IBS-C [75, 102, 103]. Similar to linaclotide, the 11%–19%), and diarrhea (12%–19%; 3%–5%) [90], all of which tend main adverse effect was diarrhea [102]. The recommended dose is to occur early after treatment initiation. Prucalopride is currently 3 mg daily, but the drug is not available in Europe. approved in a number of countries for treatment of CC in women who have failed laxative treatment [96]. The current recommended dose is 2 mg once daily. It has also been used safely in the elderly 4.4 | Future therapies where a lower dose of 1 mg per day is recommended. No studies have tested the efficacy and safety of prucalopride in IBS-C. It has been known for decades that deconjugated bile salts increase

Velusetrag is another selective 5-HT4 agonist that stimulates colonic motility and secretion and, if present in excessive amounts, colonic motility and transit, and in a 4-week phase II dose-ranging lead to diarrhea [104]. With the description of the ileal bile acid study has been shown to increase spontaneous bowel movements transporter (IBAT), inhibitors of this molecule have been developed in CC [97]. Naronapride has also been studied in a single randomized and one, elobixibat, has been subjected to phase II clinical trials in controlled phase II trial and shown to be effective in CC [98]; these CC with encouraging results [104, 105]. Not only did this agent result results have been published in abstract form only. Side effects were in relief of constipation but also one of its “side effects” included generally minor, with headache being the most frequent problem [95]. a reduction in low-density lipoprotein cholesterol. At higher doses, abdominal cramping and diarrhea were, as would be predicted, prob- lematic [104]. Akin to the prosecretory agents, systemic absorption 4.3 | Prosecretory agents is minimal. In a further randomized, double-blind, placebo-controlled 2-week phase III study in Japan, elobixibat was shown to be effec- The first of these agents was lubiprostone, a bicyclic fatty acid that tive; a 52-week open-label extension found it to be well tolerated activates a specific chloride channel (CLC-2) located on the apical with diarrhea and abdominal pain being the most common side ef- membrane of the enterocyte. Activation leads to an indirect activa- fects [105]. No studies have been conducted in IBS-C. tion of Na⁺-K⁺-Cl− cotransport, increasing water secretion into the in- Tenapanor, a small molecule with minimal systemic availability, testinal lumen. Clinical studies on intestinal and colonic transit, and is a first-in-class sodium-hydrogen exchanger 3 (NHE3) inhibitor intestinal sensory function, have not been consistent [99]. However, that acts in the gut to increase luminal sodium and water, and in a phase III RCTs have demonstrated its efficacy in CC [99]. Used for up phase 2 study in patients with IBS-C (but not, as yet, in CC) demon- to 52 weeks, lubiprostone has demonstrated a good safety profile strated efficacy [106, 107]. Mizagliflozin is a sodium-glucose–linked overall [100]. Nevertheless, given that lubiprostone is not systemi- transporter 1 (SGLT1) inhibitor that increases luminal glucose and cally absorbed, it was surprising that nausea was the most common water. This has also demonstrated efficacy in CC in a phase II study; adverse effect followed by diarrhea [100]. The recommended dose diarrhea and abdominal distension were the most notable adverse for CC is 24 µg twice daily. Similar results have been obtained in effects [108]. IBS-C patients, and in this case, the recommended dosage is 8 µg twice daily [75]. At present, lubiprostone is only available in the United States, Canada, Switzerland, India, and Japan. 4.5 | Areas for future research The other prosecretory agents are guanylate cyclase-C (GC- C) agonists. Linaclotide, a 14-amino acid peptide, and plecanatide 1. While there are now a number of prescription drug options (structurally highly similar to the physiological agonists of GC-C re- in FC and IBS-C, their relative efficacy is unknown and com- ceptors, uroguanylin and guanylin) bind to and activate guanylate cy- parative studies between these medications and against more clase-C on the luminal surface of the intestinal epithelium. Activation traditional and cheaper approaches (laxatives, fibers, etc.) are of GC-C generates cyclic guanosine monophosphate, which, in turn, needed. activates the cystic fibrosis transmembrane conductance regulator 2. It is still not clear whether stimulant laxatives and prokinetics are chloride channel, increasing the secretion of Cl- and HCO3 and the equally effective in FC and IBS-C. rate of plasma-lumen water flux; the net effect being an augmenta- 3. “Real-life” studies combining therapies (whether they are pharma- tion of stool volume [98]. cological, dietary, microbial, or behavioral) are needed. Linaclotide has been shown to accelerate intestinal transit in man 4. Constipation sufferers frequently complain of developing toler- and reduce visceral afferent traffic in laboratory animals [101]. In ance to various medications—the true nature of this phenomenon phase III studies, linaclotide has been shown to be effective in CC and its management deserve further investigation. 8 of 15 | CORSETTI et al.

5 | SURGICAL OPTIONS evacuation disorder [111] is more controversial, although there is agreement that management should initially focus on treating this The role of surgery is governed by establishing the dominant rather than by resecting the colon. pathophysiology in terms of symptom generation. Surgery has a role in patients with refractory constipation associated with colonic inertia, when this is not part of a panenteric motility disorder. 5.2 | Sacral neuromodulation Surgery also has a role in the correction of pelvic floor prolapse where it is deemed to be causing symptoms. However, given the Sacral neuromodulation (SNM) is an established treatment for pa- risk of potential harm and irreversibility of most procedures, sur- tients with urinary retention, urinary incontinence, and fecal in- gery should only be considered when all conservative measures continence. Studies in the urological field have observed that some have failed [109]. patients report improved bowel function. A prospective, multicenter study showed that patients with CC can benefit from SNM with increased episodes of successful defecation, reduction in sensation 5.1 | Colonic resection of incomplete evacuation, reduction in abdominal pain and bloating, and sustained improvement in patient visual analog scores being Colectomy should only be considered for patients with refractory achieved in a cohort of patients with mixed pathophysiologies, that symptoms, proven generalized slow colonic transit, and an absence is, slow transit and/or evacuation disorders [113]. of a list of relative contraindications (see below). However, even in Two subsequent randomized, double-blinded, crossover stud- this well-selected group, before considering colectomy, a safe and ies have shown no significant difference between sham and active potentially reversible option is a loop ileostomy. While little pub- stimulation in patients with slow-transit constipation [114, 115]. lished evidence supports this approach, it is widely practiced due to Nevertheless, SNM has been reported to improve rectal sensitivity concerns of potential for harm if the patient progresses directly to to balloon distension in patients with CC and rectal hyposensitivity colectomy [109]. In addition, the procedure is potentially reversible [116], indicating that the clinical effects seen in some patients may if significant upper GI symptoms (suggestive of upper GI dysmotility) thus be related to modulation of afferent pathways. Further stud- or significant abdominal pain and bloating (suggesting a diagnosis of ies are required to determine whether it is this patient group that is IBS) persist or worsen (as they often do after colectomy). If a stoma most likely to respond to therapy. provides relief of symptoms but there is a subsequent wish for res- toration of bowel continuity, colectomy and ileorectal anastomosis is the procedure with the greatest supporting evidence (observational 5.3 | Antegrade continence enema (ACE) only, but >50 published series). Segmental colonic resection may be considered if there are concerns about diarrhea and incontinence; ACEs can be used to achieve antegrade colonic irrigation through however, this will involve a trade-off with a higher risk of ongoing either a tube caecostomy or appendicostomy (Malone procedure) constipation [110]. [117]. Good clinical outcomes have been reported in children with Colonic resection is reported to improve constipation and spina bifida or slow-transit constipation [118]; however, adults quality of life in 50%–100% of patients [111], but may not improve and patients with colonic dysmotility have lower published suc- other symptoms such as abdominal pain and bloating. However, in cess rates [118]. Stoma stenosis is common in adults and often the majority of studies, outcomes have not been evaluated using requires surgical revision [118]. In patients with refractory slow- validated questionnaires [111]. Complications occurred in ap- transit constipation, an (ACE) conduit is an alternative to loop proximately 24% of patients. Recurrent episodes of small bowel ileostomy but best considered in non-obese patients with their obstruction occurred in about 15% of patients in the long term, appendix in situ. with significant burden of rehospitalization and frequent recourse to further surgery [111]. Patients may also experience diarrhea, urgency, and potentially fecal incontinence. In attempt to reduce 5.4 | Stoma postoperative diarrhea, total colectomy with an antiperistaltic cecorectal anastomosis has been proposed [112]. A recent prospec- Stoma creation for intractable constipation is generally considered a tive observational study of 42 patients found improved outcomes last resort. Sigmoid colostomy can be used when outlet obstruction by shortening the length of the preserved ascending colon above cannot otherwise be managed; however, persisting pelvic discom- the ileocecal junction [112]. fort coupled with diversion proctitis can give poor outcomes [119]. A Relative contraindications to colectomy include the following: loop ileostomy may be used as a temporary or long-term solution in major upper GI symptoms (proven dysmotility is an absolute con- patients with slow transit (see above). Patients should be aware that traindication) [111]; significant abdominal pain and bloating; and stoma complications are common and reintervention may be neces- poor anal sphincter function. Such findings push more strongly to- sary; however, up to 70% of patients are satisfied with the interven- ward ileostomy rather than resection. An untreated concomitant tion, despite a 20% reoperation rate [120]. CORSETTI et al. | 9 of 15

5.5 | Rectal suspension 5.8 | Areas for future research

Rectopexy with or without mesh support of the middle compartment of the pelvis has become the preferred approach in Europe in treating 1. The evidence base relating to surgical options for those with rectal intussusception [121, 122]. A SRMA of 18 observational studies refractory constipation remains slim and suffers from many provided data on outcomes of laparoscopic rectopexy in 1238 patients limitations. High-quality prospective studies are needed: (mostly high-grade rectal intussusception) with median follow-up of 25 months [123]. Improvement in constipation was achieved in 86% a. To guide optimal patient selection for colectomy or pelvic of patients [123]. Data on adverse outcomes were inconsistently re- floor/anorectal interventions ported with morbidity rates of 5%–15% and anatomical recurrence in b. To compare outcomes from various approaches to the man- about 2%–7% of the patients [123]. Further, 0.5% of patients experi- agement of the patient with dyssynergic defecation with or enced late complications due to mesh infection/erosion [123]. Most without rectal prolapse surgical experts would only consider this intervention in high-grade c. To define the role of surgical expertise/experience in outcomes intussusception, that is, at least Oxford grade III (apex of the prolapse d. To assess the additive value of a multidisciplinary approach to to the top of the anal canal). In some countries (e.g., UK), laparoscopic the patient with refractory constipation ventral mesh rectopexy requires enhanced consent (for mesh risk) and a mandatory registration on a national database [124]. 6 | THE MANAGEMENT ALGORITHM

5.6 | Rectal excisional procedures Figure 1 presents a pragmatic algorithm designed to guide the clini- cian in their practice. The management of patients with CC starts Transanal resection of intussuscepting rectal wall with or without from a correct diagnosis. First step is the exclusion of organic dis- rectocele resection may be achieved by the STARR (stapled transa- ease and of relevant secondary causes, including opioid use (opioid- nal rectal resection) procedures. A recent SRMA identified 47 stud- induced constipation is not included in this algorithm) as reported ies (3 poor-quality RCTs and observational data) of outcomes in in Panel A. 8340 patients [125]. Mean follow-up was 1.9 years. Overall morbid- The information collected during clinical evaluation then guides ity rate was 17%, with lower rates observed after the Trans-STARR the selection of appropriate medications, with preference ideally procedure (9%). No mortality was reported, and while inconsistently given to those with proven efficacy in placebo-controlled clinical tri- reported, good or satisfactory outcome occurred in 73%–80% of pa- als (Panel B). In this respect, it is important to consider the spectrum tients, with a reduction of 53–91% in obstructive defecation score. of symptom presentation and review the response to each treat- The most common long-term adverse outcome was fecal urgency, ment. It is indeed known that in IBS-C, some medications (e.g., PEG) occurring in up to 10% of patients, and long-term pain in about 2% can lead to improvement in constipation without improving abdom- of patients. These outcomes have reduced its former popularity. inal pain [83]. In some countries, it is recommended to review treat- Recurrent prolapse occurred in 4.3% of patients. ment response after 4–8 weeks when using more expensive drugs such as prucalopride and linaclotide [127]. If there is no response to a single agent, combinations can be considered either before or after 5.7 | Recto-vaginal reinforcement procedures further investigations. Medications with complementary mechanisms of action (ie, osmotic laxative or secretagogue with a stimulant These procedures are normally considered in patients with rectocele. laxative or prokinetic) can be combined. A recent SRMA identified 43 articles (three RCTs and 40 observational In the absence of an internationally recognized definition of studies) on outcomes of reinforcement of the rectal vaginal septum in refractory CC, in a recent publication, some of the authors of the 3346 patients [126]. Outcomes did not significantly vary between sur- present review suggested a practical definition [53]: “an inadequate gical approaches (vaginal, perineal, and anal). Seventy-eight percent improvement in constipation symptoms, as evaluated by an objective of patients reported a satisfactory or good outcome, with 30%–50% scale, despite adequate therapy (i.e., pharmacological or behavioral), experiencing reduced symptoms of straining, incomplete emptying, for a minimum duration of 4 weeks for each drug, and 3 months for or reduced vaginal digitation. Complications were reported after 7%– pelvic floor biofeedback therapy.” The 4-week criterion was cho- 17% of procedures. Postoperative bleeding was uncommon (0%–4%) sen in recognition that most patients who respond to medications as was hematoma or sepsis (0%–2%). Fistulation did not occur in most for CC generally do so within 4 weeks, and this is also reflected in studies. Two procedure-related deaths were observed. Overall, 17% NICE guidance [53]. In that publication, the use of a yet-to-be val- of patients developed anatomical recurrence. The use of mesh did not idated clinical decision-making tool was proposed [53]. However, confer an outcome advantage and in vaginal repair was deleterious. the result of a recent study suggests that the modified version of There was insufficient evidence to prefer one type of procedure over the Patient Assessment of Constipation-Symptom could better cap- another or relate outcome to size of rectocele. ture the complex and multifactorial patient's response to treatment 10 of 15 | CORSETTI et al.

Panel (A) Constipation FIGURE 1 Algorithm for the management of patients with constipation. Panel A, evaluation to Medical history, physical examination and DRE confirm the presence of a functional bowel disorder. Panel B, pharmacological Alarm features No alarm features and medical options. Panel C, management of patients not responding to pharmacological treatment. Panel D, Investigate for organiccausesof Identify lifestylefactors and potential constipation, includingcolorectal secondary causes of constipation when to consider surgical options cancer (including opioid-induced Absent constipation) and treat appropriately Present

Constipation persists Treat appropriately

Functional Constipation Algorithm

Panel (B) Chronic Constipation

Whatdo you mean by constipation? Questions to better characterise Infrequent bowelmovements,difficult defecationor constipation both?How many bowelmovement per week/month? What Bristol StoolForm? Is constipationassociated Pain relieved/related to defecationsuggests with abdominal pain? IBS-C; pain/doscomfort presents aftermany days of no bowelmovements canoccurrinFC No Yes

FC IBS-C Patientcan move betweenFC and IBS-Cover time

Review lifestyle modification (fibre, fluid, exercise, probiotics)*

Durationof treatment PEG (1-2 sachets daily) In IBS-C, consider before declaring a antispasmodics or failure: 4-8 weeks Combine with bisacodyl or picosulfate neuromodulators in case (5 mg 1-2 tablets daily or suppositories) constipationimproves but abdominal pain persists Switch to prucalopride 1-2 mg daily, or Linaclotide 290 µg or other and is dominantsymptom combine with laxatives secretagogues

Linaclotide 145 µg or othersecretagogues

Panel (C) Chronic constipation refractory to pharmacological treatment

Anorectal function testing (balloon expulsion test, defecography, rectal sensory testing and anorectal Obvious clinical evidence of manometry) overt pelvic organ prolapse 1

Functional defecationdisorder abnormalnormal Colonic/ wholegut transit +/- defaecography* +/-adjunctive tests e.g. urodynamics Biofeedback or alternativeaccording to local normal abnormal expertise no response

Re-evaluation of symptom- MDT to discuss surgical response investigation correlation to focus on optionsand alternative furtherpharmacology (panel B) or management strategies other untried interventions (Panel D) Follow-up or discharge

MDT to discuss surgical optionsand alternative No surgical target defined management strategies

Generalised slow transit Discuss alternatives after re- constipation without absolute and focussed discussion including relative contraindications to surgical transanal irrigation, untried intervention behavioural interventions and combinedmedications

Loopileostomy or ACE Posterior compartment prolapse Posterior compartment prolapse syndrome with high grade syndrome with dominant rectocele intussusception +/-rectocoele +/-intussusception Relief of symptoms with ileostomy but does not want permanent stoma Consider laparoscopic ventral Rectocele repair viatransvaginal or +/- 1 Colectomy and ileo-rectal rectopexy or alternative e.g. transanal route adjuncts +/- 1 anastomosis STARR adjuncts CORSETTI et al. | 11 of 15

[128]. It should be remembered that in patients with CC, symptom 6.1 | Areas for future research improvement does not always equate to satisfaction with treatment [128, 129]. 1. Critically evaluate the feasibility of this algorithm in everyday The next step (Panel C) in patients with persistent symptoms is to clinical practice perform anorectal function testing, which may include defecography (a 2. Measure its implementation and resultant impact on patient test that enables the dynamic evaluation of the process of defecation outcomes. and of the possible presence of anatomical alterations) [130], the balloon expulsion test (a test that has been demonstrated to be predictive of response to biofeedback) [46], sensory response to rectal disten- 7 | CONCLUSIONS sion, and manometry to evaluate anorectal coordination and anal motor function. If these tests indicate the presence of a functional defecation The literature accumulated over the last 10 years on CC manage- disorder, the patient should be referred for biofeedback. A functional ment has certainly added important evidence to guide clinical prac- defecation disorder may reflect problems of coordination (addressed tice. Biofeedback has been recognized as valuable treatment option predominantly by classical biofeedback), muscle weakness (addressed for functional defecation disorders, some pharmacological treat- mainly by pelvic floor muscle therapy), and rectal sensation (addressed ments have been demonstrated to be more effective than placebo, in some centers by sensory forms of biofeedback) or combinations and the surgical literature has been extensively reviewed to identify thereof. Although unsupported by RCT evidence, transanal irrigation gaps in the current knowledge. In contrast, there are some areas is a further option [47]. The evaluation of anorectal function can also where systematic review of the literature still reveals uncertainties, be considered earlier in the pathway in centers that have easy access as reported in the areas for future research paragraphs. to these investigations and biofeedback. Evaluation of colonic/whole gut transit can be used to further define underlying pathophysiology. CONFLICT OF INTEREST However, all investigations have some limitations as recently MC acted as consultant for Allergan, Arena, Kyowa Kirin, and Sanofi. pointed out [131, 132]. It is therefore important that the results of AE has served on advisory boards in the last 3 years for Kyowa Kirin, diagnostic testing are considered in the context of the “holistic” clin- Shionogi, Takeda. MH has received research funding from MacGregor ical evaluation of the individual patient. It should also be remem- Healthcare Ltd. CK is a paid consultant and speaker for Medtronic Inc. bered that psychological distress is common in patients with CC and, He has consulted in the last 3 years for Coloplast, Enteromed, and in particular, among patients with evacuation disorders [133]. Alimentary Health. He has received funding for research activities If all test results are normal, medical therapy should be re-eval- from Saluda medical, Cook Medical, Exero Medical, and Takeda. He uated and alternative approaches to management may be required. is a member of committees that benefit from industry sponsorship If abnormal, further decisions on possible management options, in- including the Rome Foundation and The GI physiology International cluding surgery, should be taken in the context of a multidisciplinary Working Group. GC acted as Consulter/Speaker for Kyowa Kirin, team (MDT) (Panel D). The composition of such MDT meetings var- Shionogi, and is member of the Anorectal Committee of the Rome ies internationally but should clearly include colorectal surgeon(s) Foundation. MRF has acted as a paid consultant and has been paid for with appropriate expertise. This approach will only be relevant in a speaking and reimbursed for attending a symposiums by Medtronic, minority of patients with constipation. Reckitt Benckiser, and Shire Pharmaceuticals. MRF has received For patients considered for surgical intervention, all information funding of research and support of staff by Medtronic, Mui Scientific, from comprehensive assessment (symptoms, physical examination, Reckitt Benckiser, and Nestle International. MRF has organized edu- and investigations) are synthesized, previous treatments reviewed, cational activities that have been supported by Medtronic, Sandhill and all other factors that might influence surgical decision making con- Scientific Instruments, and Medical Measurement Systems. MS re- sidered. Multidisciplinary decision making is influenced by the com- ceived unrestricted research grants from Danone Nutricia Research, position of the team and by accuracy and thoroughness of presented Glycom, and Ferring Pharmaceuticals; acted as Consultant/Advisory information. While it certainly offers some reassurance of a balanced Board member for Danone Nutricia Research, Nestlé, Menarini, decision, whether this improves clinical outcome remains to be proven. Biocodex, Genetic Analysis AS, Glycom, Arena, and Shire; and was The MDT must distinguish patients with a modifiable surgical part of the speakers’ bureau of Tillotts, Menarini, Kyowa Kirin, target from those in whom there is no detectable or surgically cor- Takeda, Shire, Biocodex, Alimentary Health, AlfaSigma, and Falk rectable anomaly, and those unsuitable for intervention for other Foundation. WW is a former member of the Rome Foundation. He reasons (e.g., high surgical risk). The presence of substantial un- oversaw development of the Rome IV Diagnostic Questionnaire and derlying psychological or behavioral issues should also be assessed received a Rome Foundation Grant to validate the diagnostic crite- systematically, as these factors are a relative contraindication to ria and design survey questions; these were adapted for the global surgery. In practice, two main patient groups may be considered for survey. WW is also the recipient of a National Institute of Health surgical intervention based on target pathophysiology, those with Grant to compare treatments for severe forms of fecal incontinence slow-transit constipation unresponsive to non-surgical interventions (U01 DK115575). ED has received an education grant from Alpro, re- and those with significant posterior compartment prolapse. search funding from the British Dietetic Association, Almond Board 12 of 15 | CORSETTI et al.

5. Mearin F, Ciriza C, Minguez M, et al. Clinical Practice Guideline: of California, International Nut and Dried Fruit Council, and Nestec irritable bowel syndrome with constipation and functional consti- Ltd and has served as a consultant for Puratos. EMMQ served as a pation in the adult. Rev Esp Enferm Dig. 2016;108:332-363. consultant to 4D Pharma, Alimentary Health, Allergan, Biocodex, 6. Ford AC, Moayyedi P, Lacy BE, et al. American College of Ironwood, Menarini, Pharmasierra, Salix, and Vibrant; received re- Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J search support from: 4D Pharma, Takeda, Vibrant, Zealand; and holds Gastroenterol. 2014;109(Suppl 1):S2-S26. equity in Alimentary Health. RS has received research grants from 7. Marciani L, Cox EF, Hoad CL, et al. Postprandial changes in small Sanofi-Aventis and Zespri International and speaker fees from Alfa bowel water content in healthy subjects and patients with irritable Wassermann. KW has received research funding from government bowel syndrome. Gastroenterology. 2010;138:469-477. 8. Hebden JM, Blackshaw E, D'Amato M, Perkins AC, Spiller RC. bodies including National Institute of Health Research and Medical Abnormalities of GI transit in bloated irritable bowel syndrome: Effect of Research Council; from charities including Crohn's and Colitis UK, for bran on transit and symptoms. Am J Gastroenterol. 2002;97:2315-2320. Crohn's, the Leona M. and Harry B. Helmsley Charitable Trust, and 9. Arffmann S, Andersen JR, Hegnhoj J, Schaffalitzky de Muckadell Kenneth Rainin Foundation; and from industrial sources including OB, Mogensen NB, Krag E. The effect of coarse wheat bran in the irritable bowel syndrome. A double-blind cross-over study. Scand J Almond Board of California, Clasado Biosciences, Danone, and the Gastroenterol. 1985;20:295-298. International Dried Fruit and Nut Council. KW is the coinventor of 10. Payler DK, Pomare EW, Heaton KW, Harvey RF. The effect of a mobile application to support people following dietary restrictions wheat bran on intestinal transit. Gut. 1975;16:209-213. (FoodMaestro). SMS has received honoraria for teaching for Laborie. 11. McIntyre A, Vincent RM, Perkins AC, Spiller RC. Effect of bran, ispaghula, and inert plastic particles on gastric emptying and The remaining authors have not conflict of interest. small bowel transit in humans: the role of physical factors. Gut. 1997;40:223-227. AUTHOR CONTRIBUTIONS 12. Francis CY, Whorwell PJ. Bran and irritable bowel syndrome: time MC and SMS wrote Introduction section. AE, GC, WW, and MH for reappraisal. Lancet. 1994;344:39-40. 13. Marteau P, Flourie B, Cherbut C, et al. Digestibility and bulking ef- wrote Behavioral and conservative interventions section. ED, KW, fect of ispaghula husks in healthy humans. Gut. 1994;35:1747-1752. and EMMQ wrote Manipulating the microbiome section. AE, AF, 14. Erdogan A, Rao SS, Thiruvaiyaru D, et al. Randomised clinical trial: RS, EMMQ, MS, and MC wrote Medical therapies section. TD, PG, Mixed soluble/insoluble fibre vs. psyllium for chronic constipation. UG, PRO, and ABW wrote Surgical options section. MC, MF, CK, SB, Aliment Pharmacol Ther. 2016;44:35-44. SMS, MS, RS, and EMMQ wrote The management algorithm sec- 15. Suares NC, Ford AC. Systematic review: the effects of fibre in the management of chronic idiopathic constipation. Aliment Pharmacol tion. MC revised the initial manuscript. All authors performed the Ther. 2011;33:895-901. literature search, wrote Areas for future research section, critically 16. Fenn GC, Wilkinson PD, Lee CE, Akbar FA. A general practice revised subsequent versions of the manuscript, and approved the study of the efficacy of Regulan in functional constipation. Br J final version of the manuscript. Gen Pract. 1986;40:192-197. 17. Ashraf W, Park F, Lof J, Quigley EM. Effects of psyllium therapy on stool characteristics, colon transit and anorectal function in chronic ORCID idiopathic constipation. Aliment Pharmacol Ther. 1995;9:639-647. Maura Corsetti https://orcid.org/0000-0003-2957-4684 18. Badiali D, Corazziari E, Habib FI, et al. Effect of wheat bran in Mark Fox https://orcid.org/0000-0003-4394-5584 treatment of chronic non-organic constipation. A double-blind controlled trial. Dig Dis Sci. 1995;40:349-356. Alexander C. Ford https://orcid.org/0000-0001-6371-4359 19. Hongisto SM, Paajanen L, Saxelin M, Korpela R. A combination of Robin Spiller https://orcid.org/0000-0001-6371-4500 fibre-rich rye bread and yoghurt containing Lactobacillus GG im- Kevin Whelan https://orcid.org/0000-0001-5414-2950 proves bowel function in women with self-reported constipation. William E. Whitehead https://orcid.org/0000-0001-6587-7602 Eur J Clin Nutr. 2006;60:319-324. 20. Christodoulides S, Dimidi E, Fragkos KC, Farmer AD, Whelan K, S. Mark Scott https://orcid.org/0000-0002-7997-1533 Scott SM. Systematic review with meta-analysis: effect of fibre supplementation on chronic idiopathic constipation in adults. REFERENCES Aliment Pharmacol Ther. 2016;44:103-116. 1. Cook IJ, Talley NJ, Benninga MA, Rao SS, Scott SM. Chronic 21. Voderholzer WA, Schatke W, Mühldorfer BE, Klauser AG, constipation: overview and challenges. Neurogastroenterol Motil. Birkner B, Müller-Lissner SA. Clinical response to dietary 2009;21(Suppl 2):1-8. fiber treatment of chronic constipation. Am J Gastroenterol. 2. 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